Dokument: Einfluss der interzellulären Kommunikation von Hepatozyten und Makrophagen auf die Reaktion von Makrophagen gegenüber Cytomegalieviren
| Titel: | Einfluss der interzellulären Kommunikation von Hepatozyten und Makrophagen auf die Reaktion von Makrophagen gegenüber Cytomegalieviren | |||||||
| Weiterer Titel: | Influence of intercellular communication of hepatocytes and macrophages on the response of macrophages to cytomegaloviruses | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65086 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240304-130254-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Wieland, Björn [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. med. Bode, Johannes G. [Gutachter] PD Dr. med. Reifenberger, Julia [Gutachter] | |||||||
| Stichwörter: | Makrophagen, Hepatozyten, Kokultur, Zytomegalievirus | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Die vorliegende Arbeit befasst sich mit der Fragestellung, ob Hepatozyten die Reaktion von Makrophagen auf eine Stimulation beeinflussen und inwieweit hier Unterschiede zwischen viralen und bakteriellen Pathogenen bestehen. Hierfür wurde in einem in vitro System der Einfluss von Lipopolysaccharid (LPS) und abgetötetem murinem Cytomegalievirus (MCMV) auf monokultivierte Makrophagen und Makrophagen im Ko-Kultursystem mit primären Hepatozyten verglichen. Des Weiteren wurde überprüft, ob der VLDL Rezeptor der Makrophagen an der interzellulären Kommunikation zwischen beiden Zelltypen entscheidend beteiligt ist. Die Analysen erfolgten mittels eines in der Arbeitsgruppe validierten Ko-Kultur Systems, welches die Untersuchung der Interaktion mittels löslicher Faktoren zwischen primären Hepatozyten und Bone-marrow derived macrophages (BMDMs) ermöglicht, eine direkte Zell-Zellinteraktion jedoch nicht. Um eine mögliche funktionelle Veränderung der Makrophagen infolge der Ko-Kultivierung zu analysieren wurden dem System LPS, ein bakterielles Endotoxin bzw. abgetötete Cytomegalieviren zugefügt. Dafür wurden mehrere Versuche durchgeführt, die zum einen Expressionsunterschiede zu verschiedenen Zeitpunkten nach der Stimulation verglichen und zum anderen Expressionsunterschiede nach verschiedenen Kulturzeiten bei gleicher Stimulationsdauer untersuchten.
Eine Reaktionsänderung trat zwischen 2-24 Stunden Kulturdauer ein. Im Vergleich zwischen Mono- und Ko-Kultur reagierten die kokultivierten BMDMs sowohl nach LPS als auch nach CMV Stimulation mit einer reduzierten Expression von TNFα, IL-6 bei zugleich erhöhter Expression von IL-10 mRNA. Die Daten legen somit nahe, dass die Präsenz von Hepatozyten die Reaktion von BMDMs sowohl auf virale wie auch auf bakterielle Pathogene und somit Pathogen-unabhängig dahingehend beeinflusst, dass die Expression pro-inflammatorischer Zytokine eher supprimiert wird, während anti-inflammatorische Mechanismen und hierbei insbesondere die Expression von IL-10 verstärkt wird. Soweit vergleichbar, war jedoch auffällig, dass die Reaktion von BMDM auf die verschiedenen Pathogene substanziell voneinander differierte, wobei bakterielle Pathogene wie LPS führend die Expression von TNFα und IL-6 mRNA induzierten, während die Reaktion auf virale Pathogene durch Expression von insbesondere IL-10, IFNβ, iNOS, CXCL9 und CXCL10 mRNA charakterisiert war. Dabei legen die Untersuchungen an VLDL-Rezeptor defizienten BMDMs nahe, dass diesem keine entscheidende Rolle für den Einfluss von Hepatozyten auf die Reaktion bzw. den Aktivierungszustand von Makrophagen zukommt.The present study addresses the question of how hepatocytes influence macrophage differentiation and thus their response in the context of infection. For this purpose, the influence of lipopolysaccharide (LPS) and murine cytomegalovirus (MCMV) on monocultured macrophages and macrophages in a co-culture system with primary hepatocytes was compared in an in vitro system. Furthermore, it was examined whether the VLDL receptor of macrophages is decisively involved in the intercellular communication between both cell types. The analyses were performed using a co-culture system validated in the research group, which allows the investigation of the interaction by means of soluble factors between primary hepatocytes and bone marrow derived macrophages (BMDMs). In order to analyse a possible functional change of the macrophages as a result of co-cultivation, LPS, a bacterial endotoxin or killed cytomegaloviruses were added to the system. For this purpose, several experiments were carried out, comparing expression differences at different times after stimulation on the one hand, and examining expression differences after different culture times with the same stimulation duration on the other hand. A change in response occurred between 2-24 hours of culture. In the comparison between mono- and co-culture, the co-cultured BMDMs reacted with decreased TNFα, IL-6 and increased IL-10 mRNA levels after both LPS and CMV stimulation. Thus, the co-cultured BMDMs showed similar anti-inflammatory responses to the different stimulants. This results in a pathogen- and virus-permissive situation due to the influence of the macrophages on the hepatocytes. In contrast, the basic response of BMDMs to the different stimulants differed greatly. After LPS stimulation, mono- and co-cultured BMDMs reacted with particularly strongly increased TNFα and IL-6 mRNA production, whereas after MCMV stimulation BMDMs produced increased IL-10, IFNβ, iNOS, CXCL9 and CXCL10 mRNA. The experiments with VLDL receptor-depleted BMDMs showed no significant differences from the wild type in both flow cytometry and mRNA expression measurements. Based on current data, it can therefore be assumed that the VLDL receptor does not have a decisive influence on hepatocyte-macrophage communication. | |||||||
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| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Bezug: | 05.02.2017-27.02.2024 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 04.03.2024 | |||||||
| Dateien geändert am: | 04.03.2024 | |||||||
| Promotionsantrag am: | 23.05.2023 | |||||||
| Datum der Promotion: | 22.02.2024 |
